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The resolution of lymphedema by interstitial flow in the mouse tail skin.

Abstract
Lymphangiogenesis is considered a promising approach for increasing fluid drainage during secondary lymphedema. However, organization of lymphatics into functional capillaries may be dependent upon interstitial flow (IF). The present study was undertaken to determine the importance of lymphangiogenesis for lymphedema resolution. We created a lymphatic obstruction that produces lymphedema in mouse tail skin. The relatively scar-free skin regeneration that occurred across the obstruction allowed the progression of lymphangiogenesis to be observed and compared with the evolution of lymphedema. The role of vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3 signaling in lymphedema resolution was investigated by exogenous administration of VEGF-C or neutralizing antibodies against VEGFR-3. VEGF-C protein improved lymphedema at 15 days [reducing dermal thickness from 742 +/- 105 to 559 +/- 141 microm with 95% confidence intervals (CIs), P < 0.05] without increasing lymphatic capillary coverage (11.6 +/- 6.4% following VEGF-C treatment relative to 9.6 +/- 6.2% with 95% CIs, P > 0.50). Blocking VEGFR-3 signaling did not inhibit lymphedema resolution at 25 days (dermal thickness of 462 +/- 127 microm following VEGFR-3 inhibition relative to 502 +/- 87 microm with 95% CIs) or inhibit IF, although VEGFR-3 blocking prevented lymphangiogenesis (reducing lymphatic coverage to 0.2 +/- 0.7% relative to 8.7 +/- 7.3% with 95% CIs, P < 0.005). A second mouse tail lymphedema model was employed to investigate the ability of VEGF-C to increase fluid drainage across a scar. We found that neither neutralization of VEGFR-3 nor administration of VEGF-C affected the course of skin swelling over 25 days. These findings suggest that resolution of lymphedema in the mouse tail skin may be more dependent upon IF and regeneration of the extracellular matrix across the obstruction than lymphatic capillary regeneration.
AuthorsJoseph Uzarski, Megan B Drelles, Sara E Gibbs, Emily L Ongstad, Julie C Goral, Katherine K McKeown, Alisha M Raehl, Melissa A Roberts, Bronislaw Pytowski, Martyn R Smith, Jeremy Goldman
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 294 Issue 3 Pg. H1326-34 (Mar 2008) ISSN: 0363-6135 [Print] United States
PMID18203849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antibodies, Blocking
  • Vascular Endothelial Growth Factor A
  • Receptors, Vascular Endothelial Growth Factor
Topics
  • Animals
  • Antibodies, Blocking (pharmacology)
  • Extracellular Fluid (physiology)
  • Female
  • Fluorescent Antibody Technique
  • Immunohistochemistry
  • Lymphangiogenesis (physiology)
  • Lymphedema (pathology, physiopathology)
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
  • Regeneration
  • Skin (pathology, physiopathology)
  • Tail
  • Vascular Endothelial Growth Factor A (metabolism, pharmacology)

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